CN104761523A - Phenyl C-glucoside derivative containing 3-oxoglucose structure, preparation method and uses thereof - Google Patents
Phenyl C-glucoside derivative containing 3-oxoglucose structure, preparation method and uses thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to the field of diabetes-related drugs, specifically to a class of 3-oxoglucose structure-containing phenyl C-glucoside structure type 2 sodium-glucose cotransporter (SGLT2) inhibitors, a preparation method, a drug composition containing the inhibitor, and applications of the inhibitors in preparation of diabetes drugs. The formula I is defined in the instruction, wherein R1 is selected from H, F, Cl, Br, I, C1-C3 alkyl, OR3 and SR4, R2 is selected from C1-C5 alkyl and OR5, and R3-R5 are selected from C1-C5 alkyl.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes.Specifically, the present invention relates to and contain 2 type sodium glucose cotransporter (SGLT2) inhibitor of the phenyl C-glucoside structure of 3-oxo glucose structure and preparation method thereof to diabetes are medicative, and contain their pharmaceutical composition.
Background technology
Whole world diabetic subject at present nearly about 1.7 hundred million, wherein about the overwhelming majority is II type (i.e. non-insulin-depending type) diabetic subject.N1,N1-Dimethylbiguanide class, sulfonylurea, insulin type, thiazolidinediones, alpha-glucosidase inhibitor class and dipeptidyl peptidase-iv inhibitor class medicine is mainly contained at present at the antidiabetic medicine of Clinical practice, these medicines have good therapeutic action, but there is safety issue in long-term treatment, as: liver toxicity, some drugs still has the problems such as body weight increase.
2 type sodium glucose cotransporter (SGLT2) are the novel targets of the treatment diabetes of discovered in recent years.SGLT2 is mainly distributed in renal proximal tubules, and its effect absorbs the glucose in urine, and returns it in blood, therefore suppresses that SGLT2's just can reduce the concentration of glucose in blood, and this method reduces glucose level from the past different approach.When SGLT2 function is obstructed, in urine, more glucose will be secreted, this glucose level that will contribute to diabetic subject and keep correct.Because SGLT2 inhibitor stays out of glucose metabolism, it can as the means of supplementing out economy of glycemic control main stream approach.
Chinese patent CN200610093189.9 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, A is O, S, NH, (CH
2)
n, n=0-3.
Chinese patent CN200380110040.1 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, A is covalent linkage, O, S, NH, (CH
2)
n, n=1-3.
Chinese patent CN200480006761.2 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, X is covalent linkage or low-grade alkylidene.
The invention discloses a class containing the phenyl C-glucoside analog derivative of 3-oxo glucose structure as novel SGLT2 inhibitor, these compounds can be used for preparing the medicine for the treatment of diabetes particularly diabetes B.
Summary of the invention
An object of the present invention is the shortcoming and defect overcoming prior art, provide one to have excellent activity, there is the compound of general formula I and pharmaceutically can accept prodrug ester.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for pharmaceutically acceptable prodrug ester thereof.
Another object of the present invention be to provide compound containing general formula I and pharmaceutically acceptable prodrug ester as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carrier, vehicle or thinners, and the application in treatment diabetes.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula (I) has following structural formula:
Wherein,
R
1be selected from H, F, Cl, Br, I, C
1-C
3alkyl, OR
3and SR
4;
R
2be selected from C
1-C
5alkyl and OR
5;
Wherein, R
3-R
5be selected from C
1-C
5alkyl.
Preferred following general formula (I) compound,
Wherein,
R
1be selected from F, Cl, Me, OMe and SMe;
R
2be selected from C
1-C
3alkyl and OR
5;
Wherein, R
5be selected from C
1-C
3alkyl.
More preferably the compound of general formula (I) has following structure,
General formula of the present invention (I) compound is synthesized by following route:
Compound II per uses phenyl aldehyde or benzaldehyde dimethyl acetal process to obtain compound III under acid catalysis, and described acid is selected from various mineral acid and organic acid, preferred methylsulfonic acid, camphorsulfonic acid, tosic acid and sulfuric acid; Compound III uses protecting group PG to protect 3-OH to obtain compound IV, described PG is selected from TBDMS (t-Butyldimethylsilyl), TBDPS (tert-butyl diphenyl is silica-based) and TIPS (triisopropylsilyl), and corresponding reagent is respectively TBDMSCl (TERT-BUTYL DIMETHYL CHLORO SILANE), TBDPSCl (tert-butyl diphenyl chlorosilane) and TIPSCl (tri isopropyl chlorosilane); Compound IV uses and uses MeOCH in the presence of a base
2cl process obtains compound V, and described alkali is selected from organic bases, preferred triethylamine and diisopropyl ethyl amine; Compound V sloughs protecting group and obtains compound VI, and the reagent used is selected from TBAF, HF pyridine, HF triethylamine; Compound VI oxidation obtains compound VI I, and oxidizing condition is selected from Ac
2o/DMSO, (COCl)
2/ DMSO/Et
3n, PCC (pyridinium chlorochromate) and PDC (pyridiniumdichromate), preferred Ac
2o/DMSO; Compound VI I sloughs protecting group in presence of an acid, obtains Compound I, and described acid is selected from various mineral acid and organic acid, preferred methylsulfonic acid, camphorsulfonic acid, tosic acid and sulfuric acid; Wherein, R
1and R
2definition as previously mentioned.
The pharmaceutically acceptable prodrug ester of formula I of the present invention, comprises the ester that any one or more hydroxyl in molecule and ethanoyl, pivaloyl group, various phosphoryl, formamyl, alkoxyl formyl etc. are formed.
Formula I of the present invention, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carrier, vehicle or thinner.This pharmaceutical composition can make the formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention, described pharmacy or bromatology can accept auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle.
Composition of the present invention, described pharmacy or bromatology can accept auxiliary material.Weighting agent is the composition of one or more that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose; Described tackiness agent comprises the composition of one or more of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises the composition of one or more of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Compound of Formula I of the present invention has the restraining effect of SGLT2, can be used as the medicine of effective constituent for the preparation of diabetes aspect.The activity of compound of Formula I of the present invention is by glucose in urine modelling verification.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
Embodiment 1
1-[the chloro-3-of 4-(4-ethoxy benzyl) phenyl]-1-deoxidation-3-oxo-beta-D-Glucopyranose (I-1)
A.
The DMF of 20.44g (50mmol) Compound II per-1,22.83g (150mmol) benzaldehyde dimethyl acetal, 3g camphorsulfonic acid (CSA) and 120mL drying is added in the round-bottomed flask of a 250mL, then heat up to stir at 60 DEG C and spend the night, TLC shows reaction to be completed.
Be poured in 400mL frozen water after reaction mixture cool to room temperature, stir, with 200mL × 3 dichloromethane extraction.Merge organic phase, use saturated NaHCO successively
3solution and brine It, anhydrous sodium sulfate drying, boils off solvent on a rotary evaporator, and the resistates obtained, through column chromatography purification, obtains product III-1.White solid, 182-183 DEG C.Productive rate 83%.
1H NMR(DMSO-d
6,400MHz)δ:7.45-7.47(m,2H,Ar-H),7.36-7.40(m,4H,Ar-H),7.28(d,1H,J=1.6Hz,Ar-H),7.21(dd,1H,J=2.0Hz and8.4Hz,Ar-H),7.08(d,2H,J=8.8Hz,Ar-H),6.83(d,2H,J=8.4Hz,Ar-H),5.60(s,1H,PhCHO
2),5.31(d,1H,J=3.6Hz,OH),5.13(d,1H,J=5.6Hz,OH),4.16-4.22(m,2H),3.94-3.99(m,4H),3.65-3.70(m,1H),3.50-3.51(m,3H),3.24-3.28(m,1H),1.29(t,3H,J=6.8Hz,OCH
2CH
3).
B.
The DMF of 19.88g (40mmol) compound III-1,8.17g (120mmol) imidazoles and 140mL drying is added in the round-bottomed flask of a 250mL drying, stir under ice-water bath cooling, slowly drip solution prepared by the methylene dichloride that is dissolved in 10mL drying by 6.63g (44mmol) TERT-BUTYL DIMETHYL CHLORO SILANE (TBDMSCl), dropwise rear reaction mixture and at room temperature stir and spend the night.TLC shows reaction to be completed.
Reaction mixture is poured in 400mL frozen water, stirs, with 200mL × 3 dichloromethane extraction.Merge organic phase, with brine It, anhydrous sodium sulfate drying, boil off solvent on a rotary evaporator, the resistates obtained, through column chromatography purification, obtains product IV-1.White foam solid.Productive rate 92%.
1H NMR(DMSO-d
6,400MHz)δ:7.35-7.46(m,6H,Ar-H),7.29(s,1H,Ar-H),7.21-7.25(m,1H,Ar-H),7.09(d,2H,J=8.4Hz,Ar-H),6.83(d,2H,J=8.4Hz,Ar-H),5.62(s,1H,PhCHO
2),5.09(d,1H,J=7.6Hz,OH),4.23(d,1H,J=9.6Hz,sugar H-1),4.16-4.20(m,1H),3.94-4.02(m,4H),3.70(q,2H,J=8.8Hz),3.48-3.58(m,2H),3.25-3.29(m,1H),1.29(t,3H,J=7.0Hz,OCH
2CH
3),0.81(s,9H,SiMe
3),0.03(s,3H,SiMe),-0.01(s,3H,SiMe).
C.
21.39g (35mmol) mixture IV-1,11.27g (140mmol) CH is added in the round-bottomed flask of a 250mL
3oCH
2the methylene dichloride of Cl, 45.23g (350mmol) diisopropyl ethyl amine (DIPEA) and 150mL drying, reaction mixture stirs and flows through night next time, and TLC detection reaction completes.
100mL dchloromethane is used after reaction mixture cool to room temperature, once use dilute hydrochloric acid and the saturated common salt water washing of 100mL saturated aqueous common salt, 200mL5%, anhydrous sodium sulfate drying, boils off solvent on a rotary evaporator, the resistates obtained, through column chromatography purification, obtains product V-1.White foam solid.Productive rate 75%.
1H NMR(DMSO-d
6,400MHz)δ:7.40-7.44(m,3H),7.36-7.38(m,3H),7.33(d,1H,J=2.0Hz),7.29(dd,1H,J=1.8Hz and8.2Hz),7.09(d,2H,J=8.8Hz),6.82(d,2H,J=8.4Hz),5.60(s,1H),4.50(d,1H,J=6.4Hz),4.37(d,1H,J=9.6Hz),4.25(d,1H,J=6.0Hz),4.16(dd,1H,J=4.2Hz and10.2Hz),3.91-3.99(m,5H),3.67(t,1H,J=9.8Hz),3.54-3.64(m,3H),2.38(s,3H),1.28(t,3H,J=7.0Hz),0.78(s,9H),-0.01(s,3H),-0.05(s,3H).
D.
The THF of 13.11g (20mmol) mixture V-1 and 100mL drying is added in the round-bottomed flask of a 250mL, then at room temperature stir, add the THF solution of the tetra-n-butyl Neutral ammonium fluoride (TBAF) of 40mL (40mmol) 1M, dropwise rear stirred at ambient temperature 6 hours, TLC shows reaction to be completed.
Reaction mixture is poured in 400mL frozen water, stirs, with 150mL × 3 dichloromethane extraction.Merge organic phase, with brine It, anhydrous sodium sulfate drying, boil off solvent on a rotary evaporator, the resistates obtained, through column chromatography purification, obtains product VI-1.White foam solid.Productive rate 90%.
1H NMR(DMSO-d
6,400MHz)δ:7.36-7.47(m,6H),7.31(s,1H),7.25(d,1H,J=8.4Hz),7.08(d,2H,J=8.4Hz),6.82(d,2H,J=8.4Hz),5.60(s,1H),5.50(d,1H,J=5.2Hz),4.59(d,1H,J=6.4Hz),4.32(d,1H,J=9.6Hz),4.14-4.19(m,2H),3.94-4.03(m,4H),3.65-3.73(m,2H),3.47-3.58(m,3H),2.55(s,3H),1.29(t,3H,J=7.0Hz).
E.
Add 8.12g (15mmol) compound VI-1 and 50mLDMSO in the round-bottomed flask of a 100mL, ice-water bath cooling is lower stirs, and slowly drips 20mL Ac
2o, dropwises rear reaction mixture and at room temperature continues stirring and spend the night, and TLC checks that reaction completes.
Reaction mixture is poured in 300mL frozen water, stirs, with 100mL × 3 dichloromethane extraction.Merge organic phase, use saturated NaHCO successively
3solution and with brine It, anhydrous sodium sulfate drying, boils off solvent on a rotary evaporator, and the resistates obtained, through column chromatography purification, obtains product VII-1.White foam solid.Productive rate 83%.
1H NMR(DMSO-d
6,400MHz)δ:7.32-7.47(m,8H),7.05(d,2H,J=8.4Hz),6.80(d,2H,J=8.8Hz),5.68(s,1H),4.74(d,1H,J=10.0Hz),4.62(d,1H,J=9.6Hz),4.48(d,1H,J=10.4Hz),4.44(d,1H,J=6.8Hz),4.31(dd,1H,J=4.2Hz and9.4Hz),4.25(d,1H,J=6.4Hz),3.98(s,2H),3.93(q,2H,J=7.1Hz),3.86(t,1H,J=9.8Hz),3.81(dd,1H,J=4.2Hz and9.8Hz),2.58(s,3H),1.26(t,3H,J=6.8Hz).
F.
Add 5.39g (10mmol) compound VI I-1 and 35mL methyl alcohol in the round-bottomed flask of a 100mL, stirred at ambient temperature, add 1g CSA, then stir at 60 DEG C and spend the night, TLC checks that reaction completes.
Be poured in 300mL frozen water after reaction mixture cool to room temperature, stir, with 100mL × 3 dichloromethane extraction.Merge organic phase, use saturated NaHCO successively
3solution and with brine It, anhydrous sodium sulfate drying, boils off solvent on a rotary evaporator, and the resistates obtained, through column chromatography purification, obtains product I-1.White foam solid.Productive rate 80%.
1H NMR(DMSO-d
6,400MHz)δ:7.41-7.43(m,2H),7.33(dd,1H,J=1.8Hz and8.2Hz),7.08(d,2H,J=8.4Hz),6.82(d,1H,J=8.8Hz),5.38(d,1H,J=6.0Hz),5.32(d,1H,J=6.0Hz),4.76(t,1H,J=6.0Hz),4.12-4.24(m,3H),3.93-3.99(m,4H),3.74(dd,1H,J=5.4Hz and10.6Hz),3.56-3.61(m,1H),3.40(dd,1H,J=3.2Hz and10.0Hz),1.28(t,3H,J=6.8Hz).
13CNMR(DMSO-d
6,100MHz)δ:207.37,156.89,138.60,138.04,132.50,131.05,130.64,129.47,128.88,127.18,114.28,83.01,82.57,76.80,72.57,62.85,61.13,37.65,14.63.
Embodiment 2-9
With reference to the operation steps of embodiment 1, prepare following compounds.
Embodiment 10
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, abundant mixing, add polyvinylpyrrolidonesolution solution, mixing, softwood processed, sieve, wet granular processed, in 50-60 DEG C of drying, by Sodium carboxymethyl starch, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
Embodiment 11
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, abundant mixing, add polyvinylpyrrolidonesolution solution, mixing, softwood processed, sieve, wet granular processed, in 50-60 DEG C of drying, by Sodium carboxymethyl starch, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
Embodiment 12
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mixes, add polyvinylpyrrolidonesolution solution, mixing, softwood processed, sieves, wet granular processed, in 50-60 DEG C of drying, Magnesium Stearate and talcum powder are sieved in advance, then joins in above-mentioned particle, encapsulated, to obtain final product.
Embodiment 13
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mixes, add polyvinylpyrrolidonesolution solution, mixing, softwood processed, sieves, wet granular processed, in 50-60 DEG C of drying, Magnesium Stearate and talcum powder are sieved in advance, then joins in above-mentioned particle, encapsulated, to obtain final product.
Embodiment 14
In distilled water, first add distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram of activated carbon, stirred at ambient temperature 20 minutes, filters, filtrate, strength of solution is determined in middle detection, by the 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes, obtains injection liquid.
Embodiment 15
In distilled water, first add distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram of activated carbon, stirred at ambient temperature 20 minutes, filters, filtrate, strength of solution is determined in middle detection, by the 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes, obtains injection liquid.
Embodiment 16
Preparation technology: get water for injection 80ml, adds main ingredient, after N.F,USP MANNITOL, lactose, poloxamer be stirred to dissolve, the Citric Acid adding 1mol/L regulates PH to 7.0-9.0, mends and adds water to 100ml.Add 0.5g gac, stir 20 minutes at 30 DEG C, de-charcoal, adopt filtering with microporous membrane degerming, filtrate carries out packing by often propping up 1ml, and pre-freeze is after 2 hours, and freezing lower drying under reduced pressure 12 hours, after to sample temperature to room temperature, dry 5 hours again, obtained white loose block, sealed and get final product.
Embodiment 17
Preparation technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, fully mixes, then take recipe quantity auxiliary material and fully mix with main ingredient.Add tackiness agent softwood again, 14 mesh sieves are granulated, 55 DEG C of dryings, the whole grain of 12 mesh sieve, measure bag and heavily pack.
Embodiment 18
The high sugar of normal SD rats height fat is fed after one month, body weight is between 200-220g/, with streptozocin low dose (10mg/kg × 3) repeatedly abdominal injection modeling (diabetes B model), measure blood-sugar content (>15mmol/L is qualified) before and after modeling.After modeling success, modeling rat is measured and body weight random packet (5/group) according to twenty-four-hour urine sugar, be respectively one group of blank group (giving equal-volume 0.5%CMC sodium solution) and some testing compound groups (15mg/kg).Fasting 16 hours before each group of rat experiment.After gavage gives experimental rat testing compound 0.5h, then gavage gives glucose (4g/kg).The urine of 0-12h time period after collection administration, with the urine sugar value of determination of glucose oxidase each time period.The results are shown in following table.
As can be seen from the above results, compound disclosed by the invention has well induction glucose in urine effect, may be used for the medicine preparing treatment diabetes B.
Claims (8)
1. there is compound and the pharmaceutically acceptable prodrug ester thereof of general formula (I) structure,
Wherein,
R
1be selected from H, F, Cl, Br, I, C
1-C
3alkyl, OR
3and SR
4;
R
2be selected from C
1-C
5alkyl and OR
5;
Wherein, R
3-R
5be selected from C
1-C
5alkyl.
2. the compound of what claim 1 defined have general formula (I) and pharmaceutically acceptable prodrug ester,
Wherein,
R
1be selected from F, Cl, Me, OMe and SMe;
R
2be selected from C
1-C
3alkyl and OR
5;
Wherein, R
5be selected from C
1-C
3alkyl.
3. the compound of Formula I that defines of claim 2, is selected from following compounds,
4. synthesize arbitrary the defined method belonging to the compound of general formula (I) of claim 1-3:
Compound II per uses phenyl aldehyde or benzaldehyde dimethyl acetal process to obtain compound III under acid catalysis, and described acid is selected from methylsulfonic acid, camphorsulfonic acid, tosic acid and sulfuric acid; Compound III uses protecting group PG to protect 3-OH to obtain compound IV, described PG is selected from TBDMS (t-Butyldimethylsilyl), TBDPS (tert-butyl diphenyl is silica-based) and TIPS (triisopropylsilyl), and corresponding reagent is respectively TBDMSCl (TERT-BUTYL DIMETHYL CHLORO SILANE), TBDPSCl (tert-butyl diphenyl chlorosilane) and TIPSCl (tri isopropyl chlorosilane); Compound IV uses and uses MeOCH in the presence of a base
2cl process obtains compound V, and described alkali is selected from triethylamine and diisopropyl ethyl amine; Compound V sloughs protecting group and obtains compound VI, and the reagent used is selected from TBAF, HF pyridine, HF triethylamine; Compound VI oxidation obtains compound VI I, and oxidizing condition is selected from Ac2O/DMSO, (COCl)
2/ DMSO/Et
3n, PCC (pyridinium chlorochromate) and PDC (pyridinium dichromate); Compound VI I sloughs protecting group in presence of an acid, obtains Compound I, and described acid is selected from methylsulfonic acid, camphorsulfonic acid, tosic acid and sulfuric acid; Wherein, R
1and R
2definition as arbitrary in claim 1-3 as described in.
5. general formula (I) compound that defines of any one of claim 1-3 and pharmaceutically acceptable salt and the application of prodrug ester in preparation treatment diabetes medicament.
6. a pharmaceutical composition, general formula (I) compound containing any one of claim 1-3 and pharmaceutically acceptable salt and prodrug ester, and suitable carrier or vehicle.
7. pharmaceutical composition according to claim 6, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
8. solid described in claim 7 and liquid oral medicine comprise: dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, and described injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060009400A1 (en) * | 2004-07-06 | 2006-01-12 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture |
US20070275907A1 (en) * | 2006-05-23 | 2007-11-29 | Yuanwei Chen | Glucose transport inhibitors and methods of use |
CN103058972A (en) * | 2013-01-17 | 2013-04-24 | 天津药物研究院 | Phenyl C-glucoside derivatives containing cyclohexane structure as well as preparation method and application thereof |
WO2016041470A1 (en) * | 2014-09-15 | 2016-03-24 | National Institute Of Biological Sciences, Beijing | Sglt-2 inhibitors |
-
2014
- 2014-01-06 CN CN201410008758.XA patent/CN104761523B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060009400A1 (en) * | 2004-07-06 | 2006-01-12 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture |
US20070275907A1 (en) * | 2006-05-23 | 2007-11-29 | Yuanwei Chen | Glucose transport inhibitors and methods of use |
CN103058972A (en) * | 2013-01-17 | 2013-04-24 | 天津药物研究院 | Phenyl C-glucoside derivatives containing cyclohexane structure as well as preparation method and application thereof |
WO2016041470A1 (en) * | 2014-09-15 | 2016-03-24 | National Institute Of Biological Sciences, Beijing | Sglt-2 inhibitors |
Non-Patent Citations (2)
Title |
---|
ZHANG SHUO ET AL.: "3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes", 《CHEM. RES. CHIN. UNIV.》 * |
万惠新 等.: "2 型糖尿病治疗靶点钠-葡萄糖共转运蛋白2 抑制剂研究进展", 《药学学报》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016041470A1 (en) * | 2014-09-15 | 2016-03-24 | National Institute Of Biological Sciences, Beijing | Sglt-2 inhibitors |
CN107108539A (en) * | 2014-09-15 | 2017-08-29 | 北京生命科学研究所 | Sodium glucose cotransporter 2 (SGLT 2) inhibitor |
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